Dramatic changes in systemic and renal hemodynamics occur during pregnancy. There is a marked decrease in systemic vascular resistance and reciprocal increases in cardiac output and global arterial compliance, accompanied by a modest decline in mean arterial pressure. The renal circulation participates in this maternal vasodilatory response, and consequently, renal plasma flow and glomerular filtration rate rise by 80 and 50%, respectively. Comparable changes, albeit of lesser magnitude occur in the maternal circulatory system during the late luteal phase of the menstrual cycle in anticipation of a pregnancy (Chapman, A. et al., 1997 “Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy” Am J Physiol 273(5 Pt 2):F777-82). Although the mechanisms underlying these maternal adaptations to pregnancy are not fully understood, there is increasing evidence that the ovarian peptide hormone relaxin plays a key role (reviewed in Conrad, K. P, 2011 “Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia” Semin Nephrol. 31(1):15-32).
Originally isolated from the ovary by Hisaw and colleagues, relaxin was named for its ability to relax the pubis symphysis in some species (Hisaw, F, 1926 “Experimental relaxation of the pubic ligament of the guinea pig” Proc Exp Biol Med 23:661-663). In non-human primates, it was subsequently shown to cause morphological changes in endothelial cells of endometrial blood vessels consistent with vascular hypertrophy and hyperplasia, and enlargement of arterioles and capillaries (Hisaw, F. L., Hisaw, F. L., Jr., and Dawson, A. B, 1967 “Effects of relaxin on the endothelium of endometrial blood vessels in monkeys (Macaca mulatta)” Endocrinology 81:375-385).
Relaxin, a corpus luteal hormone, circulates at low levels in the luteal phase of the menstrual cycle, and in pregnancy peaks during the first trimester falling to intermediate levels thereafter (Sherwood, O., 1994, Relaxin. NY: Raven. 861-1009 pp.). Experimental evidence from the pregnant rate model shows that relaxin mediates maternal cardiovascular, renal and osmoregulatory adaptations at midterm pregnancy (Novak J. et al., “Relaxin is essential for renal vasodilation during pregnancy in conscious rats.” J Clin Invest. 107:1469-1475 (2001); Debrah D O. et al., “Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats.” Endocrinol. 147:5126-31 (2006)).
Assisted reproductive technology (ART) began in 1978 with the birth of Louise Brow. Since 1978, there have been 3-4 million live births conceived by ART worldwide and the use of ART has doubled over the past decade. In 2010, there were 154,417 ART cycles performed yielding over 47,000 live births in the US. In pregnancies achieved through ART, the number of corpora lutea (CL) vary, while during a natural pregnancy, there is typically one CL. CL is typically associated with the production of: androgens, estrogen, progesterone, inhibin A, relaxin and p450scc.
In general, there are two types of ART pregnancies: those achieved by using either autologous or donor eggs. Briefly, in the case of autologous eggs, after in vitro fertilization (IVF) and fresh embryo transfer (ET), there are multiple corpora lutea (CL) secondary to the ovarian stimulation used to enhance follicle numbers. Frozen embryos can be transferred either during a natural or medicated cycle. During a natural cycle, there is typically one CL, while in a medicated cycle involving pituitary suppression, there is no CL. Donor-egg recipients may have ovarian failure or be medicated, and therefore, in either case do not have a CL. To summarize, ART can occur in the setting of nil, one or multiple CL.
Emerging epidemiological evidence suggests that pregnancies conceived by ART may be at increased risk for abnormal pregnancy outcomes including pregnancy induced hypertension and compromised fetal growth (Helmerhorst F M et al. 2004 “Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies” BMJ 328:261; Jackson R A et al. 2004 “Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis” Obstet Gynecol 103: 551-563; Keegan D A et al. 2007 “Increased risk of pregnancy-induced hypertension in young recipients of donated oocytes” Fertil Steril 87: 776-781; Maman E et al. 1998 “Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously” Fertil Steril 70: 240-245; Salha O et al. 1999 “The influence of donated gametes on the incidence of hypertensive disorders of pregnancy” Hum Reprod 14: 2268-2273; Soderstrom-Anttila V et al. 1998 “Obstetric and perinatal outcome after oocyte donation: comparison with in-vitro fertilization pregnancies” Hum Reprod 13: 483-490; and Weiss G et al. 1993 “Elevated first-trimester serum relaxin concentrations in pregnant women following ovarian stimulation predict prematurity risk and preterm delivery” Obstet Gynecol 82: 821-828). Furthermore, women and their children who suffer from these obstetrical complications may be at higher risk for future adverse cardiovascular events (Gluckman P D et al. 2008 “Effect of in utero and early-life conditions on adult health and disease” N Engl J Med 359: 61-73; Roberts J M et al. 2003 “Summary of the NHLBI working group on research on hypertension during pregnancy” Hypertension 41: 437-445; Sibai B et al. 2005 “Pre-eclampsia” Lancet 365: 785-799, 2005).
Of perhaps even greater concern is that many of the women who conceive by ART are typically of advanced maternal age, which alone may compromise cardiovascular adaptation during pregnancy. Potential explanations for adverse obstetrical outcomes following ART are (i) multiple gestations, although increased risk is observed with singleton pregnancies, (ii) increased maternal age, although increased risk is observed after matching for maternal age, (iii) underlying infertility, (iv) increased immunological challenge in the case of donor gametes, and (v) iatrogenic reasons related to embryo culture conditions. However, another possible explanation is that other naturally occurring or iatrogenic causes may contribute to adverse pregnancy outcomes, i.e., absence of a CL in donor-egg recipients or excessive number of CL after ovarian stimulation in women receiving autologous eggs.
Infusion of recombinant human relaxin-2 (rhRLX) in nonpregnant conscious female and male rats significantly decreases renal and systemic vascular resistances, and increases cardiac output, renal blood flow, glomerular filtration, and global arterial compliance, thus mimicking the circulatory changes of pregnancy (Conrad, K. P., 2011 “Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia,” Semin Nephrol., 31(1):15-32). Conversely, administration of relaxin-neutralizing antibodies or ovariectomy inhibits the circulatory changes during midterm pregnancy in conscious rats (Conrad, K. P., Semin Nephrol. supra). In addition to reductions in arterial tone and/or arterial compositional or geometrical remodeling, another likely mechanism for the decrease in systemic vascular resistance (SVR) and increase in global arterial compliance (AC) observed during relaxin administration or in pregnancy is increased maternal angiogenesis and/or vasculogenesis (Conrad, K. P., Debrah, D. O., Novak, J., Danielson, L. A., and Shroff, S. G., 2004, “Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats” Endocrinology 145:3289-3296; and Segal M. S. et al. 2012 “Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice.” Blood 119:629-36). It is hypothesized that these patients also fail to significantly increase their cardiac output above pre-pregnant levels at any gestational stage mainly due to lack of systemic vasodilation and angiogenesis/vasculogenesis, thus increasing the risk for abnormal obstetrical outcomes following conception by ART.
There is a need for effective methods in mimicking normal maternal adaptations during pregnancy, particularly CL function to restore cardiovascular adaptations of pregnancy. The present invention meets this need by providing novel methods for correcting maternal hemodynamics in subjects attempting to conceive with ART that involves donor eggs.